Visual pathway white matter alterations in glaucoma

Glaucoma is one of the leading causes of irreversible blindness worldwide. While glaucoma has been traditionally viewed as an eye disease, studies have shown that the entire visual pathway of glaucoma patients exhibits evidence of degeneration. Our understanding of the cause and structural nature of this degeneration, however, is still limited. In my thesis, I addressed this issue by utilizing cutting-edge magnetic resonance imaging (MRI) techniques to analyze white matter (WM) degeneration of the visual pathway in glaucoma patients. Additionally, I conducted the first longitudinal study of visual pathway WM degeneration in glaucoma, which is essential for understanding the source and pattern of spread of this degeneration over time.The results of my work revealed that visual pathway WM degeneration in glaucoma starts at the level of the eyes and then spreads in the direction of the brain to affect the entire visual pathway. Additionally, I found that the anterior and posterior segments of the visual pathway are not affected simultaneously by this degeneration. Rather, an observable time lag seems to exist between the degeneration of these segments along the course of the disease. This finding could have an impact on the development of novel neuroprotective and stem cell-based treatments of glaucoma. Furthermore, I found that in glaucoma patients the MRI-based measures of visual pathway WM degeneration correlate strongly with standard clinical measures. This suggests that in glaucoma, MRI could potentially serve as a complementary diagnostic tool in cases where current clinical approaches do not perform adequately

Macrostructural Changes of the Acoustic Radiation in Humans with Hearing Loss and Tinnitus Revealed with Fixel-Based Analysis

Age-related hearing loss is the most prevalent sensory impairment in the older adult population and is related to noise-induced damage or age-related deterioration of the peripheral auditory system. Hearing loss may affect the central auditory pathway in the brain, which is a continuation of the peripheral auditory system located in the ear. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus. Strikingly, investigations into the impact of acquired hearing loss, with and without tinnitus, on the human central auditory pathway are sparse. This study used diffusion-weighted imaging (DWI) to investigate changes in the largest central auditory tract, the acoustic radiation, related to hearing loss and tinnitus. Participants with hearing loss, with and without tinnitus, and a control group were included. Both conventional diffusion tensor analysis and higher-order fixel-based analysis were applied. The fixel-based analysis was used as a novel framework providing insight into the axonal density and macrostructural morphologic changes of the acoustic radiation in hearing loss and tinnitus. The results show tinnitus-related atrophy of the left acoustic radiation near the medial geniculate body. This finding may reflect a decrease in myelination of the auditory pathway, instigated by more profound peripheral deafferentation or reflecting a preexisting marker of tinnitus vulnerability. Furthermore, age was negatively correlated with the axonal density in the bilateral acoustic radiation. This loss of fiber density with age may contribute to poorer speech understanding observed in older adults. SIGNIFICANCE STATEMENT Age-related hearing loss is the most prevalent sensory impairment in the older adult population. Older individuals are subject to the cumulative effects of aging and noise exposure on the auditory system. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus: the perception of a phantom sound. In this large DWI-study, we provide evidence that in hearing loss, the additional presence of tinnitus is related to degradation of the acoustic radiation. Additionally, older age was related to axonal loss in the acoustic radiation. It appears that older adults have the aggravating circumstances of age, hearing loss, and tinnitus on central auditory processing, which may partly be because of the observed deterioration of the acoustic radiation with age

Progression of Visual Pathway Degeneration in Primary Open-Angle Glaucoma:A Longitudinal Study

Background: Primary open-angle glaucoma (POAG) patients exhibit widespread white matter (WM) degeneration throughout their visual pathways. Whether this degeneration starts at the pre- or post-geniculate pathways remains unclear. In this longitudinal study, we assess the progression of WM degeneration exhibited by the pre-geniculate optic tracts (OTs) and the post-geniculate optic radiations (ORs) of POAG patients over time, aiming to determine the source and pattern of spread of this degeneration. Methods: Diffusion-weighted MRI scans were acquired for 12 POAG patients and 14 controls at two time-points 5.4 +/- 2.1 years apart. Fiber density (FD), an estimate of WM axonal density, was computed for the OTs and ORs of all participants in an unbiased longitudinal population template space. First, FD was compared between POAG patients and the controls at time-point 1 (TP1) and time-point 2 (TP2) independently. Secondly, repeated measures analysis was performed for FD change in POAG patients between the two time-points. Finally, we compared the rate of FD change over time between the two groups. Results: Compared to the controls, POAG patients exhibited significantly lower FD in the left OT at TP1 and in both OTs and the left OR at TP2. POAG patients showed a significant loss of FD between the time-points in the right OT and both ORs, while the left OR showed a significantly higher rate of FD loss in POAG patients compared to the controls. Conclusions: We find longitudinal progression of neurodegenerative WM changes in both the pre- and post-geniculate visual pathways of POAG patients. The pattern of changes suggests that glaucomatous WM degeneration starts at the pre-geniculate pathways and then spreads to the post-geniculate pathways. Furthermore, we find evidence that the trans-synaptic spread of glaucomatous degeneration to the post-geniculate pathways is a prolonged process which continues in the absence of detectable pre-geniculate degenerative progression. This suggests the presence of a time window for salvaging intact post-geniculate pathways, which could prove to be a viable therapeutic target in the future

Investigating changes in axonal density and morphology of glaucomatous optic nerves using fixel-based analysis

PURPOSE: To characterize neurodegeneration of glaucomatous optic nerves (ONs) in terms of changes in axonal density and morphology using fixel-based analysis (FBA), a novel framework for analyzing diffusion-weighted MRI (DWI). Furthermore, we aimed to explore the potential of FBA measures as biomarkers of glaucomatous ON degeneration. METHODS: DWI scans were obtained from 15 glaucoma patients and 15 controls. ONs were tracked and segmented into their three anatomical segments; intraorbital (IO), intracanalicular (ICAN) and intracranial (ICRAN). For each segment, FBA measures were computed, which included fiber density (FD; a measure of axonal density), fiber-bundle cross-section (FC; an estimate of morphological changes), and fiber density and cross-section (FDC). Peripapillary retinal nerve fiber layer (pRNFL) thickness and visual field mean deviation (VFMD) were assessed for glaucoma patients. ANCOVA was used to compare FBA values between the two groups, and Spearman's correlation analysis was used to test the correlation between FBA measures and pRNFL thickness and VFMD. RESULTS: All glaucomatous ON segments showed a significant loss of FD and FDC compared to the controls, while a loss of FC was found in the IO and ICRAN segments only. FD and FDC values of the IO and ICAN segments of glaucomatous ONs showed significant correlations with pRNFL thickness and VFMD. CONCLUSIONS: Glaucomatous ONs exhibit lower FD and FC compared to controls, indicating axonal loss and gross atrophy. The correlation between FBA measures of glaucomatous ONs and established clinical tests of glaucoma demonstrates the potential of FBA measures as biomarkers of glaucomatous ON degeneration

Fixel-Based Analysis of Visual Pathway White Matter in Primary Open-Angle Glaucoma

Purpose: White matter (WM) degeneration of the visual pathways in primary open-angle glaucoma (POAG) is well documented, but its exact pathophysiology remains unclear. To date, glaucomatous WM degeneration has been exclusively studied using diffusion tensor imaging (DTI) only. However, DTI measures lack direct biological interpretation, and the approach itself suffers from multiple technical limitations. Fixel-based analysis (FBA) is a novel framework for studying WM degeneration, overcoming DTI's technical limitations and providing biologically meaningful metrics. FBA measures fiber density (FD), representing early microstructural changes, and fiber-bundle cross section (FC), representing late macrostructural changes. In this study, we use FBA to study glaucomatous degeneration of the pregeniculate optic tracts (OTs) and postgeniculate optic radiation (ORs) in POAG. Methods: This was a cross-sectional case-control study with 12 POAG patients and 16 controls. Multi-shell diffusion-weighted images were acquired. FBA was used to produce a population template, and probabilistic tractography was used to track the OTs and ORs in template space. Finally, FD and FC of the tracts of interest were compared between the two groups. Results: Compared with the controls, the OTs of the patients exhibited a significant (familywise error corrected P < 0.05) decrease in FD and FC, whereas their ORs exhibited a significant decrease in FD but not in FC. Conclusions: FBA provides sensitive measures to assess WM changes in glaucoma. Our findings suggest that the OTs of glaucoma patients exhibit signs of more advanced WM degeneration compared with the ORs. This potentially implicates anterograde trans-synaptic propagation as the primary cause of glaucomatous spread along the visual pathways

Influence of electromagnetic radiation emitted by daily-use electronic devices on the Eyemate (R) system in-vitro:a feasibility study

Background: Eyemate® is a system for the continual monitoring of intraocular pressure (IOP), composed of an intraocular sensor, and a hand-held reader device. As the eyemate®-IO sensor communicates with the hand-held reader telemetrically, some patients might fear that the electronic devices that they use on a daily basis might somehow interfere with this communication, leading to unreliable measurements of IOP. In this study, we investigated the effect of electromagnetic radiation produced by a number of everyday electronic devices on the measurements made by an eyemate®-IO sensor in-vitro, in an artificial and controlled environment. Methods: The eyemate®-IO sensor was suspended in a sterile 0.9% sodium chloride solution and placed in a water bath at 37 °C. The antenna, connected to a laptop for recording the data, was positioned at a fixed distance of 1 cm from the sensor. Approximately 2 hrs of "quasi-continuous"measurements were recorded for the baseline and for a cordless phone, a smart-phone and a laptop. Repeated measures ANOVA was used to compare any possible differences between the baseline and the tested devices. Results: For baseline measurements, the sensor maintained a steady-state, resulting in a flat profile at a mean pressure reading of 0.795 ± 0.45 hPa, with no apparent drift. No statistically significant difference (p = 0.332) was found between the fluctuations in the baseline and the tested devices (phone: 0.76 ± 0.41 hPa; cordless: 0.787 ± 0.26 hPa; laptop: 0.775 ± 0.39 hPa). Conclusion: In our in-vitro environment, we found no evidence of signal drifts or fluctuations associated with the tested devices, thus showing a lack of electromagnetic interference with data transmission in the tested frequency ranges